Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression

Abstract

Aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence. The induction of EMT entails the loss of epithelial characteristics and the de novo acquisition of a mesenchymal phenotype. In breast cancer, the EMT state has been associated with cancer stem cell properties including expression of the stem cell-associated CD44+/CD24-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies. Intriguingly, EMT features are also associated with stem cells isolated from the normal mouse mammary gland and human breast reduction tissues as well as the highly aggressive metaplastic and claudin-low breast tumor subtypes. This has implications for the origin of these breast tumors as it remains unclear whether they derive from cells that have undergone EMT or whether they represent an expansion of a pre-existing stem cell population that expresses EMT-associated markers to begin with. In the present review, we consider the current evidence connecting EMT and stem cell attributes and discuss the ramifications of these newly recognized links for our understanding of the emergence of distinct breast cancer subtypes and breast cancer progression.

Figure 1

Epithelial-mesenchymal transition and stem cell traits in breast cancer progression. Breast tumors may originate from the transformation of normal adult tissue stem cells or from more differentiated progenitors that have acquired self-renewal capabilities (left panel). Moreover, a subset of resident mammary gland stem cells (MaSCs, in blue) exhibit epithelial-mesenchymal transition (EMT) features a priori. The EMT features of metaplastic and claudin-low breast tumors may thus signify either that they derive from cells that have undergone EMT or that they originate from deregulated expansion of a pre-existing stem cell pool that expresses EMT-associated markers. Additionally, the induction of sporadic EMT within a tumor bestows migratory and invasive potential coupled with self-renewal capabilities to cancer cells, generating cancer stem cells (CSCs) (right panel). Following extravasation and upon encountering an altered local microenvironment, CSCs (in red) may at least partially revert to an epithelial phenotype (mesenchymal-epithelial transition (MET)) to allow adhesion and proliferation at distal sites. As sporadic EMT and MET are triggered by extracellular stimuli and microenvironment factors, this model provides a plausible explanation for the de novo generation of CSCs from differentiated tumor cells and suggests that passage through EMT and MET is an alternative and/or additional driving force in breast tumorigenesis.